HOMA-IR and non-HDL-C as predictors of high cholesteryl ester transfer protein activity in patients at risk for type 2 diabetes

doi:10.1016/j.clinbiochem.2012.02.005

Clinical Biochemistry

Volume 45, Issues 7–8, May 2012, Pages 566-570

https://doi.org/10.1016/j.clinbiochem.2012.02.005 Get rights and content

Abstract

Background and aims

Metabolic syndrome (MS) and type 2 diabetes are highly associated with an abnormal lipoprotein profile, which may be generated and accentuated by high cholesteryl ester transfer protein (CETP) activity. Given the difficulty in measuring CETP activity, the aim was to identify simple biochemical predictors of high CETP activity.

Design and methods

Eighty five subjects at risk for type 2 diabetes were classified according to the presence of MS. Lipoprotein profile, HOMA-IR and endogenous CETP activity were evaluated.

Results

As expected, MS patients presented higher concentration of glucose, insulin, triglycerides and non-HDL-C and lower HDL-C levels. Moreover, MS patients exhibited increased HOMA-IR and CETP activity. Employing a ROC curve for MS, high CETP activity was defined as > 250% ml^− 1 h^− 1. The predictive variables of high CETP were non-HDL-C ≥ 160 mg/dl (OR = 11.1;95%IC = 3.3–38.2;p < 0.001) and HOMA-IR > 2.1 (OR = 4.4;95%IC = 1.3–14.8;p < 0.05).

Conclusions

High non-HDL-C and insulin resistance were predictors for increased CETP activity which measurement is not accessible for clinical laboratories.

Highlights

► CETP measurement is not suitable for clinical laboratories. ► Increased non-HDL-C and HOMA-IR were predictors of high CETP activity. ► Identifying subjects with high CETP activity might improve CVD risk assessment.

Introduction

Metabolic syndrome (MS) and, particularly, type 2 diabetes are generally accompanied by high triglycerides (TG), low high density lipoprotein cholesterol (HDL-C) and increased small and dense-low density lipoprotein (LDL), all of them related to insulin resistance and high risk of cardiovascular disease. This so called “atherogenic dyslipemia” is primarily generated by hepatic VLDL overproduction and may be accentuated by high cholesteryl ester transfer protein (CETP), which mediates the transfer of TG from TG-rich lipoproteins to HDL and LDL in exchange for cholesteryl esters [1], [2]. It is important to note that when hypertriglyceridemia is present, CETP induces modifications in lipoprotein chemical composition, increasing the atherogenic properties of apo B-containing lipoproteins and impairing HDL antiatherogenic capacities [3], [4], [5]. In fact, in previous studies carried out both in hypertriglyceridemic and MS patients, we found that high CETP specific activity was associated with an increase in proatherogenic factors and a decrease in HDL levels and antiatherogenic functions [6], [7], [8]. Furthermore, in patients with non-alcoholic fatty liver disease [9] and even in normotriglyceridemic type 2 diabetic patients [10], [11], high CETP activity was associated to an increased prevalence of small and dense LDL particles. Based on this putative proatherogenic role of CETP, its inhibition by pharmacological agents has been proposed as a strategy to reduce cardiovascular disease [12]. Several studies carried out in small groups of patients consistently reported an increase in HDL-C levels of approximately 30–50%, but still failed to demonstrate favourable results regarding cardiovascular disease events [13]. In any case, it would be essential to measure or to estimate CETP activity, in order to ensure CETP inhibitory treatment.

Insulin resistant-associated conditions are a worldwide major disorder. The prevalence of MS in USA, employing the diagnostic criteria of the National Cholesterol Education Program Adult Treatment Panel III (ATP III) [14], was reported to be over 24% [15], [16]. In Latin America, the Cardiovascular Risk Factor Multiple Evaluation in Latin America Study (CARMELA) reported results ranging from 15 to 27% [17] and, in particular, in Buenos Aires, Argentina, it was 27 and 18% for adult men and women, respectively. Using the definition of the International Diabetes Federation (IDF) [18], this prevalence was still higher. Actually, in a previous study, we observed that the prevalence of MS screened among workers with 40 to 65 years was 39.3% in men and 29.0% in women [19]. Therefore, considering that CETP influences the risk of cardiovascular disease, evaluation of CETP activity would provide useful information of clinical relevance. Particularly, in individuals at significant risk for development of type 2 diabetes, it has been consistently and extensively reported that increased CETP activity further enhances cardiovascular disease risk, thus making these patients eligible for CETP inhibitory therapy. However, measurement of CETP activity requires complex techniques which are not easily standardized and automatized [20], thus limiting their implementation in clinical laboratories.

Considering that high CETP activity might identify subjects with increased risk of cardiovascular disease, the main aim of the present study was to identify biochemical predictors of high CETP activity commonly measured in clinical practice by standardized and precise methods in an Argentinean cohort of subjects at risk for type 2 diabetes.

Section snippets

Subjects

All subjects were inhabitants of the city of Viedma, Rio Negro, Argentina. Subjects at risk for type 2 diabetes were identified as those individuals who were older than 45 years and presented one or more of the following risk factors: a) being overweight (BMI > 25 kg/m²), b) first-degree relative with diabetes, c) hypertension, d) history of gestational diabetes, and e) physical inactivity, in accordance with ADA statement [21]. Subjects who matched any of the following criteria were excluded: a)

Results

Table 1 presents clinical and biochemical characteristics from the 86 patients at risk for type 2 diabetes selected for CETP activity measurement classified according to the presence of MS. Patients with and without MS were similar in age, sex distribution and percentage of smokers. As expected, MS patients had higher BMI, waist circumference, and diastolic and systolic blood pressure. It is worthy to note that the percentage of subjects with familial history of cardiovascular disease and

Discussion

In the present study, the main finding was the identification of simple biochemical parameters as predictors of increased CETP activity in a cohort of subjects at risk for type 2 diabetes. Results showed that high endogenous CETP activity was independently associated with non-HDL-C above 160 mg/dl and HOMA-IR over 2.1, after adjustment for several confounders. The simple and reliable determinations of non-HDL-C and HOMA-IR allowed identifying subjects with high CETP activity, which specific

Conflict of interest

The authors declare to have no conflicts of interest.

Acknowledgements

This work was supported by grants from the University of Buenos Aires [UBACYT 01/2017], from the Consejo Nacional de Investigaciones Científicas y Tecnológicas [CONICET PIP 0931] and from “Alberto J. Roemmers” Foundation. Tomás Meroño and Leonardo Gómez Rosso are research fellows from CONICET. We are grateful to Wiener-Lab and Roche Products for their collaboration.

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HOMA-IR and non-HDL-C as predictors of high cholesteryl ester transfer protein activity in patients at risk for type 2 diabetes

Abstract

Background and aims

Design and methods

Results

Conclusions

Highlights

Introduction

Section snippets

Subjects

Results

Discussion

Conflict of interest

Acknowledgements

J Lipid Res

Lancet

Clin Chim Acta

Atherosclerosis

Atherosclerosis

Clin Chim Acta

Atherosclerosis

Atherosclerosis

J Am Coll Cardiol

Metabolism

Atherosclerosis

J Clin Lipidol

Alterations in high-density lipoprotein metabolism and reverse cholesterol transport in insulin resistance and type 2 diabetes mellitus: role of lipolytic enzymes, lecithin:cholesterol acyltransferase and lipid transfer proteins

Eur J Clin Invest

Why is HDL functionally deficient in type 2 diabetes?

Curr Diab Rep

Metabolic syndrome is associated with elevated oxidative stress and dysfunctional dense high-density lipoprotein particles displaying impaired antioxidative activity

J Clin Endocrinol Metab

Anacetrapib and dalcetrapib: two novel cholesteryl ester transfer protein inhibitors

Ann Pharmacother

Dalcetrapib: a review of Phase II data

Expert Opin Investig Drugs

Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report

Circulation